tbuckley/cabot-search huggingface dataset:
Genomics of Secondarily Temperate Adaptation in the Only Non-Antarctic Icefish
Authors: Angel G Rivera-Colón, Niraj Rayamajhi, Bushra Fazal Minhas, Giovanni Madrigal, Kevin T Bilyk, Veronica Yoon, Mathias Hüne, Susan Gregory, C H Christina Cheng, Julian M Catchen
Journal: Molecular Biology and Evolution (2023)

Abstract White-blooded Antarctic icefishes, a family within the adaptive radiation of Antarctic notothenioid fishes, are an example of extreme biological specialization to both the chronic cold of the Southern Ocean and life without hemoglobin. As a result, icefishes display derived physiology that limits them to the cold and highly oxygenated Antarctic waters. Against these constraints, remarkably one species, the pike icefish Champsocephalus esox, successfully colonized temperate South American waters. To study the genetic mechanisms underlying secondarily temperate adaptation in icefishes, we generated chromosome-level genome assemblies of both C. esox and its Antarctic sister species, Champsocephalus gunnari. The C. esox genome is similar in structure and organization to that of its Antarctic congener; however, we observe evidence of chromosomal rearrangements coinciding with regions of elevated genetic divergence in pike icefish populations. We also find several key biological pathways under selection, including genes related to mitochondria and vision, highlighting candidates behind temperate adaptation in C. esox. Substantial antifreeze glycoprotein (AFGP) pseudogenization has occurred in the pike icefish, likely due to relaxed selection following ancestral escape from Antarctica. The canonical AFGP locus organization is conserved in C. esox and C. gunnari, but both show a translocation of two AFGP copies to a separate locus, previously unobserved in cryonotothenioids. Altogether, the study of this secondarily temperate species provides an insight into the mechanisms underlying adaptation to ecologically disparate environments in this otherwise highly specialized group.
Effects of Sociodemographic Characteristics, Comorbidity, and Coexposures on the Association between Air Pollution and Type 2 Diabetes: A Nationwide Cohort Study
Authors: Mette Sørensen, Aslak Harbo Poulsen, Ulla Arthur Hvidtfeldt, Jesper H. Christensen, Jørgen Brandt, Lise Marie Frohn, Matthias Ketzel, Christopher Andersen, Victor H. Valencia, Christina Funch Lassen, Ole Raaschou-Nielsen
Journal: Environmental Health Perspectives (2023)

Exposure to air pollution has been associated with a higher risk of type 2 diabetes (T2D), but studies investigating whether deprived groups are more susceptible to the harmful effects of air pollution are inconsistent.We aimed to investigate whether the association between air pollution and T2D differed according to sociodemographic characteristics, comorbidity, and coexposures.We estimated residential exposure to PM2.5, ultrafine particles (UFP), elemental carbon, and NO2 for all persons living in Denmark in the period 2005-2017. In total, 1.8 million persons 50-80 y of age were included for main analyses of whom 113,985 developed T2D during follow-up. We conducted additional analyses on 1.3 million persons age 35-50 y. Using Cox proportional hazards model (relative risk) and Aalens additive hazard model (absolute risk), we calculated associations between 5-y time-weighted running means of air pollution and T2D in strata of sociodemographic variables, comorbidity, population density, road traffic noise, and green space proximity.Air pollution was associated with T2D, especially among people age 50-80 y, with hazard ratios of 1.17 [95% confidence interval (CI): 1.13, 1.21] per 5 μg/m3PM2.5 and 1.16 (95% CI: 1.13, 1.19) per 10,000 UFP/cm3. In the age 50-80 y population, we found higher associations between air pollution and T2D among men in comparison with women, people with lower education vs. individuals with high education, people with medium income vs. those with low or high income, people cohabiting vs. those living alone, and people with comorbidities vs. those without comorbidities. We observed no marked changes according to occupation, population density, road noise, or surrounding greenness. In the age 35-50 y population, similar tendencies were observed, except in relation to sex and occupation, where we observed associations with air pollution only among women and blue-collar workers.We found stronger associations between air pollution and T2D among people with existing comorbidities and weaker associations among people with high socioeconomic status in comparison with those with lower socioeconomic status. https://doi.org/10.1289/EHP11347.
Pathogenic human variant that dislocates GATA2 zinc fingers disrupts hematopoietic gene expression and signaling networks
Authors: Mabel Minji Jung, Siqi Shen, Giovanni A. Botten, Thomas Olender, Koichi R. Katsumura, Kirby D. Johnson, Alexandra A. Soukup, Peng Liu, Qingzhou Zhang, Zena D. Jensvold, Peter W. Lewis, Robert A. Beagrie, Jason K.K. Low, Lihua Yang, Joel P. Mackay, Lucy A. Godley, Marjorie Brand, Jian Xu, Sunduz Keles, Emery H. Bresnick
Journal: Journal of Clinical Investigation (2023)

Although certain human genetic variants are conspicuously loss of function, decoding the impact of many variants is challenging. Previously, we described a patient with leukemia predisposition syndrome (GATA2 deficiency) with a germline GATA2 variant that inserts 9 amino acids between the 2 zinc fingers (9aa-Ins). Here, we conducted mechanistic analyses using genomic technologies and a genetic rescue system with Gata2 enhancer-mutant hematopoietic progenitor cells to compare how GATA2 and 9aa-Ins function genome-wide. Despite nuclear localization, 9aa-Ins was severely defective in occupying and remodeling chromatin and regulating transcription. Variation of the inter-zinc finger spacer length revealed that insertions were more deleterious to activation than repression. GATA2 deficiency generated a lineage-diverting gene expression program and a hematopoiesis-disrupting signaling network in progenitors with reduced granulocyte-macrophage colony-stimulating factor (GM-CSF) and elevated IL-6 signaling. As insufficient GM-CSF signaling caused pulmonary alveolar proteinosis and excessive IL-6 signaling promoted bone marrow failure and GATA2 deficiency patient phenotypes, these results provide insight into mechanisms underlying GATA2-linked pathologies.
Local senolysis in aged mice only partially replicates the benefits of systemic senolysis
Authors: Joshua N. Farr, Dominik Saul, Madison L. Doolittle, Japneet Kaur, Jennifer L. Rowsey, Stephanie J. Vos, Mitchell N. Froemming, Anthony B. Lagnado, Yi Zhu, Megan Weivoda, Yuji Ikeno, Robert J. Pignolo, Laura J. Niedernhofer, Paul D. Robbins, Diana Jurk, João F. Passos, Nathan K. LeBrasseur, Tamara Tchkonia, James L. Kirkland, David G. Monroe, Sundeep Khosla
Journal: Journal of Clinical Investigation (2023)

Clearance of senescent cells (SnCs) can prevent several age-related pathologies, including bone loss. However, the local versus systemic roles of SnCs in mediating tissue dysfunction remain unclear. Thus, we developed a mouse model (p16-LOX-ATTAC) that allowed for inducible SnC elimination (senolysis) in a cell-specific manner and compared the effects of local versus systemic senolysis during aging using bone as a prototype tissue. Specific removal of Sn osteocytes prevented age-related bone loss at the spine, but not the femur, by improving bone formation without affecting osteoclasts or marrow adipocytes. By contrast, systemic senolysis prevented bone loss at the spine and femur and not only improved bone formation, but also reduced osteoclast and marrow adipocyte numbers. Transplantation of SnCs into the peritoneal cavity of young mice caused bone loss and also induced senescence in distant host osteocytes. Collectively, our findings provide proof-of-concept evidence that local senolysis has health benefits in the context of aging, but, importantly, that local senolysis only partially replicates the benefits of systemic senolysis. Furthermore, we establish that SnCs, through their senescence-associated secretory phenotype (SASP), lead to senescence in distant cells. Therefore, our study indicates that optimizing senolytic drugs may require systemic instead of local SnC targeting to extend healthy aging.
Effectiveness of Bedaquiline Use beyond Six Months in Patients with Multidrug-Resistant Tuberculosis
Authors: Letizia Trevisi, Miguel A. Hernán, Carole D. Mitnick, Uzma Khan, Kwonjune J. Seung, Michael L. Rich, Mathieu Bastard, Helena Huerga, Nara Melikyan, Sidney A. Atwood, Zaza Avaliani, Felix Llanos, Mohammad Manzur-ul-Alam, Khin Zarli, Amsalu Bekele Binegdie, Sana Adnan, Arusyak Melikyan, Alain Gelin, Afshan K. Isani, Dmitry Vetushko, Zhenisgul Daugarina, Patrick Nkundanyirazo, Fauziah Asnely Putri, Charles Vilbrun, Munira Khan, Catherine Hewison, Palwasha Y. Khan, Molly F. Franke
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Current recommendations for the treatment of rifampicin- and multidrug-resistant tuberculosis include bedaquiline (BDQ) used for 6 months or longer. Evidence is needed to inform the optimal duration of BDQ.
Association of Neighborhood-Level Household Income With 21-Gene Recurrence Score and Survival Among Patients With Estrogen Receptor–Positive Breast Cancer
Authors: Sung Jun Ma, Jasmin Gill, Olivia Waldman, Keerti Yendamuri, Cynthia Dunne-Jaffe, Udit Chatterjee, Fatemeh Fekrmandi, Rohil Shekher, Austin Iovoli, Song Yao, Oluwadamilola T. Oladeru, Anurag K. Singh
Journal: JAMA Network Open (2023)

While low income has been associated with a higher incidence of triple-negative breast cancer, its association with 21-gene recurrence score (RS) among patients with estrogen receptor (ER)-positive breast cancer remains unclear.To evaluate the association of household income with RS and overall survival (OS) among patients with ER-positive breast cancer.This cohort study used data from the National Cancer Database. Eligible participants included women diagnosed between 2010 and 2018 with ER-positive, pT1-3N0-1aM0 breast cancer who received surgery followed by adjuvant endocrine therapy with or without chemotherapy. Data analysis was performed from July 2022 to September 2022.Low vs high neighborhood-level household income levels defined as below vs above the median household income of $50 353 based on each patient's zip code.RS (a score ranged from 0 to 100 based on gene expression signatures indicating the risk of distant metastasis, with RS of 25 or below indicating non-high risk and RS above 25 indicating high risk) and OS.Among 119 478 women (median [IQR] age, 60 [52-67] years; 4737 [4.0%] Asian and Pacific Islander, 9226 [7.7%] Black, 7245 [6.1%] Hispanic, 98 270 [82.2%] non-Hispanic White), 82 198 (68.8%) and 37 280 (31.2%) patients had high and low income, respectively. Logistic multivariable analysis (MVA) showed that, compared with high income, low income was associated with higher RS (adjusted odds ratio [aOR], 1.11; 95% CI, 1.06-1.16). Cox MVA showed that low income was also associated with worse OS (adjusted hazards ratio [aHR], 1.18; 95% CI, 1.11-1.25). Interaction term analysis showed a statistically significant interaction between income levels and RS (interaction P < .001). On subgroup analysis, significant findings were noted among those with RS below 26 (aHR, 1.21; 95% CI, 1.13-1.29), while there was no significant OS difference between income levels among others with RS of 26 or higher (aHR, 1.08; 95% CI, 0.96-1.22).Our study suggested that low household income was independently associated with higher 21-gene recurrence scores and significantly worse survival outcomes among those with scores below 26, but not 26 or higher. Further studies are warranted to investigate the association between socioeconomic determinants of health and intrinsic tumor biology among patients with breast cancer.
Using Haplotype-Based Artificial Intelligence to Evaluate SARS-CoV-2 Novel Variants and Mutations
Authors: Lue Ping Zhao, Seth Cohen, Michael Zhao, Margaret Madeleine, Thomas H. Payne, Terry P. Lybrand, Daniel E. Geraghty, Keith R. Jerome, Lawrence Corey
Journal: JAMA Network Open (2023)

Importance Earlier detection of emerging novel SARS-COV-2 variants is important for public health surveillance of potential viral threats and for earlier prevention research. Artificial intelligence may facilitate early detection of SARS-CoV2 emerging novel variants based on variant-specific mutation haplotypes and, in turn, be associated with enhanced implementation of risk-stratified public health prevention strategies. Objective To develop a haplotype-based artificial intelligence (HAI) model for identifying novel variants, including mixture variants (MVs) of known variants and new variants with novel mutations. Design, Setting, and Participants This cross-sectional study used serially observed viral genomic sequences globally (prior to March 14, 2022) to train and validate the HAI model and used it to identify variants arising from a prospective set of viruses from March 15 to May 18, 2022. Main Outcomes and Measures Viral sequences, collection dates, and locations were subjected to statistical learning analysis to estimate variant-specific core mutations and haplotype frequencies, which were then used to construct an HAI model to identify novel variants. Results Through training on more than 5 million viral sequences, an HAI model was built, and its identification performance was validated on an independent validation set of more than 5 million viruses. Its identification performance was assessed on a prospective set of 344 901 viruses. In addition to achieving an accuracy of 92.8% (95% CI within 0.1%), the HAI model identified 4 Omicron MVs (Omicron-Alpha, Omicron-Delta, Omicron-Epsilon, and Omicron-Zeta), 2 Delta MVs (Delta-Kappa and Delta-Zeta), and 1 Alpha-Epsilon MV, among which Omicron-Epsilon MVs were most frequent (609/657 MVs [92.7%]). Furthermore, the HAI model found that 1699 Omicron viruses had unidentifiable variants given that these variants acquired novel mutations. Lastly, 524 variant-unassigned and variant-unidentifiable viruses carried 16 novel mutations, 8 of which were increasing in prevalence percentages as of May 2022. Conclusions and Relevance In this cross-sectional study, an HAI model found SARS-COV-2 viruses with MV or novel mutations in the global population, which may require closer examination and monitoring. These results suggest that HAI may complement phylogenic variant assignment, providing additional insights into emerging novel variants in the population.
History of Low Hourly Wage and All-Cause Mortality Among Middle-aged Workers
Authors: Katrina L. Kezios, Peiyi Lu, Sebastian Calonico, Adina Zeki Al Hazzouri
Journal: JAMA (2023)

Importance Earning a low wage is an increasingly recognized public health concern, yet little research exists on the long-term health consequences of sustained low-wage earning. Objective To examine the association of sustained low-wage earning and mortality in a sample of workers with hourly wage reported biennially during peak midlife earning years. Design, Setting, and Participants This longitudinal study included 4002 US participants, aged 50 years or older, from 2 subcohorts of the Health and Retirement Study (1992-2018) who worked for pay and reported earning hourly wages at 3 or more time points during a 12-year period during their midlife (1992-2004 or 1998-2010). Outcome follow-up occurred from the end of the respective exposure periods until 2018. Exposures Low-wage—less than the hourly wage for full-time, full-year work at the federal poverty line—earning history was categorized as never earning a low wage, intermittently earning a low wage, and sustained earning a low wage. Main Outcomes and Measures Cox proportional hazards and additive hazards regression models sequentially adjusted for sociodemographics, and economic and health covariates were used to estimate associations between low-wage history and all-cause mortality. We examined interaction with sex or employment stability on multiplicative and additive scales. Results Of the 4002 workers (aged 50-57 years at the beginning of exposure period and 61-69 years at the end), 1854 (46.3%) were female; 718 (17.9%) experienced employment instability; 366 (9.1%) had a history of sustained low-wage earning; 1288 (32.2%) had intermittent low-wage earning periods; and 2348 (58.7%) had never earned a low wage. In unadjusted analyses, those who had never earned low wages experienced 199 deaths per 10 000 person-years, those with intermittent low wages, 208 deaths per 10 000 person-years, and those with sustained low wages, 275 deaths per 10 000 person-years. In models adjusted for key sociodemographic variables, sustained low-wage earning was associated with mortality (hazard ratio [HR], 1.35; 95% CI, 1.07-1.71) and excess deaths (66; 95% CI, 6.6-125); these findings were attenuated with additional adjustments for economic and health covariates. Significant excess death and elevated mortality risk were observed for workers with sustained low-wage exposure and employment fluctuations (eg, for sustained low-wage × employment fluctuated, HR, 2.18; 95% CI, 1.35-3.53; for sustained low-wage × stable employment, HR, 1.17; 95% CI, 0.89,-1.54; P for interaction = .003). Conclusions and Relevance Sustained low-wage earning may be associated with elevated mortality risk and excess deaths, especially when experienced alongside unstable employment. If causal, our findings suggest that social and economic policies that improve the financial standing of low-wage workers (eg, minimum wage laws) could improve mortality outcomes.
Glioblastoma and Other Primary Brain Malignancies in Adults
Authors: Lauren R. Schaff, Ingo K. Mellinghoff
Journal: JAMA (2023)

Importance Malignant primary brain tumors cause more than 15 000 deaths per year in the United States. The annual incidence of primary malignant brain tumors is approximately 7 per 100 000 individuals and increases with age. Five-year survival is approximately 36%. Observations Approximately 49% of malignant brain tumors are glioblastomas, and 30% are diffusely infiltrating lower-grade gliomas. Other malignant brain tumors include primary central nervous system (CNS) lymphoma (7%) and malignant forms of ependymomas (3%) and meningiomas (2%). Symptoms of malignant brain tumors include headache (50%), seizures (20%-50%), neurocognitive impairment (30%-40%), and focal neurologic deficits (10%-40%). Magnetic resonance imaging before and after a gadolinium-based contrast agent is the preferred imaging modality for evaluating brain tumors. Diagnosis requires tumor biopsy with consideration of histopathological and molecular characteristics. Treatment varies by tumor type and often includes a combination of surgery, chemotherapy, and radiation. For patients with glioblastoma, the combination of temozolomide with radiotherapy improved survival when compared with radiotherapy alone (2-year survival, 27.2% vs 10.9%; 5-year survival, 9.8% vs 1.9%; hazard ratio [HR], 0.6 [95% CI, 0.5-0.7]; P &amp;amp;lt; .001). In patients with anaplastic oligodendroglial tumors with 1p/19q codeletion, probable 20-year overall survival following radiotherapy without vs with the combination of procarbazine, lomustine, and vincristine was 13.6% vs 37.1% (80 patients; HR, 0.60 [95% CI, 0.35-1.03]; P = .06) in the EORTC 26951 trial and 14.9% vs 37% in the RTOG 9402 trial (125 patients; HR, 0.61 [95% CI, 0.40-0.94]; P = .02). Treatment of primary CNS lymphoma includes high-dose methotrexate-containing regimens, followed by consolidation therapy with myeloablative chemotherapy and autologous stem cell rescue, nonmyeloablative chemotherapy regimens, or whole brain radiation. Conclusions and Relevance The incidence of primary malignant brain tumors is approximately 7 per 100 000 individuals, and approximately 49% of primary malignant brain tumors are glioblastomas. Most patients die from progressive disease. First-line therapy for glioblastoma is surgery followed by radiation and the alkylating chemotherapeutic agent temozolomide.
Aspirin Discontinuation at 24 to 28 Weeks’ Gestation in Pregnancies at High Risk of Preterm Preeclampsia
Authors: Manel Mendoza, Erika Bonacina, Pablo Garcia-Manau, Monica López, Sara Caamiña, Àngels Vives, Eva Lopez-Quesada, Marta Ricart, Anna Maroto, Laura de Mingo, Elena Pintado, Roser Ferrer-Costa, Lourdes Martin, Alicia Rodríguez-Zurita, Esperanza Garcia, Mar Pallarols, Laia Vidal-Sagnier, Mireia Teixidor, Carmen Orizales-Lago, Adela Pérez-Gomez, Vanesa Ocaña, Linda Puerto, Pilar Millán, Mercè Alsius, Sonia Diaz, Nerea Maiz, Elena Carreras, Anna Suy
Journal: JAMA (2023)

Aspirin reduces the incidence of preterm preeclampsia by 62% in pregnant individuals at high risk of preeclampsia. However, aspirin might be associated with an increased risk of peripartum bleeding, which could be mitigated by discontinuing aspirin before term (37 weeks of gestation) and by an accurate selection of individuals at higher risk of preeclampsia in the first trimester of pregnancy.To determine whether aspirin discontinuation in pregnant individuals with normal soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1:PlGF) ratio between 24 and 28 weeks of gestation was noninferior to aspirin continuation to prevent preterm preeclampsia.Multicenter, open-label, randomized, phase 3, noninferiority trial conducted in 9 maternity hospitals across Spain. Pregnant individuals (n = 968) at high risk of preeclampsia during the first-trimester screening and an sFlt-1:PlGF ratio of 38 or less at 24 to 28 weeks of gestation were recruited between August 20, 2019, and September 15, 2021; of those, 936 were analyzed (intervention: n = 473; control: n = 463). Follow-up was until delivery for all participants.Enrolled patients were randomly assigned in a 1:1 ratio to aspirin discontinuation (intervention group) or aspirin continuation until 36 weeks of gestation (control group).Noninferiority was met if the higher 95% CI for the difference in preterm preeclampsia incidences between groups was less than 1.9%.Among the 936 participants, the mean (SD) age was 32.4 (5.8) years; 3.4% were Black and 93% were White. The incidence of preterm preeclampsia was 1.48% (7/473) in the intervention group and 1.73% (8/463) in the control group (absolute difference, -0.25% [95% CI, -1.86% to 1.36%]), indicating noninferiority.Aspirin discontinuation at 24 to 28 weeks of gestation was noninferior to aspirin continuation for preventing preterm preeclampsia in pregnant individuals at high risk of preeclampsia and a normal sFlt-1:PlGF ratio.ClinicalTrials.gov Identifier: NCT03741179 and ClinicalTrialsRegister.eu Identifier: 2018-000811-26.